KR20220150464A - Pyrimidine derivative or its salt and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention provides a pyrimidine derivative or a pharmaceutically acceptable salt thereof, a method for manufacturing the same, and a pharmaceutical composition comprising the same. The pyrimidine or the pharmaceutically acceptable salt thereof can be usefully applied to the prevention or treatment of cancer, for example renal cancer, by selectively inhibiting the HIF2a-HIF1b heterodimer.

Description

Pyrimidine derivatives or salts thereof and pharmaceutical compositions containing them

The present invention relates to a pyrimidine derivative or a salt thereof and a pharmaceutical composition containing the same.

In general, renal cancer refers to renal cell carcinoma, a malignant tumor that arises in the renal parenchyma. Renal cell carcinoma accounts for about 85% of all renal tumors, and is the second most common cancer after bladder cancer among urological malignancies worldwide. According to statistics in 2014, about 64,000 new cases of kidney cancer are diagnosed every year in the United States alone, and about 70% of these are histologically clear cell type renal cell carcinoma (clear cell renal cell carcinoma), which has a very poor prognosis. one of the cancers.

As a treatment for kidney cancer that has progressed to stage 3 or 4 or higher in the advanced stage of kidney cancer, there are currently immune checkpoints such as multitargeted tyrosine kinase inhibitors, mTOR inhibitors, and PD-1 antibodies that inhibit angiogenesis. Inhibitors are widely used, but very few patients experience a complete response, and most cancers are getting worse during treatment. Since the 5-year survival rate for patients with advanced renal cell carcinoma, including metastases, is only 8%, alternatives to new targeted therapies are urgently required.

In hypoxia, a tumor microenvironment, a transcription factor called hypoxia inducible factor α (HIFα) accumulates in excess in cells. HIFα moves into the intracellular nucleus, forms heterodimerization with its binding partner, aryl hydrocarbon nuclear translocator (ARNT), and then activates target genes involved in angiogenesis, cancer metabolism, and red blood cell production, such as VEGF, It contributes to cancer growth and survival by promoting the expression of GLUT1, TGFα, and EPO.

A tumor suppressor protein called pVHL is defective in more than 90% of patients with clear cell renal cell carcinoma, mainly due to mutations, gene deletions, and epigenetic silencing of the VHL gene. pVHL is a protein constituting a part of the E3 ligase complex, and induces degradation of HIFα by recognizing and ubiquitination of HIFα which is hydroxylated under normal oxygen concentration (normoxia). Therefore, in clear cell renal cell carcinoma with defective pVHL function, HIFα accumulates in excess in cells regardless of oxygen concentration.

On the other hand, HIF1α and HIF2α, which are homologous proteins of HIFα, are present in cells, but play opposite roles when considering the progression of clear cell renal cell carcinoma (ccRCC). According to the results of previous studies, HIF2α acts as a major oncogenic driver in terms of tumor progression and maintenance, whereas HIF1α acts as a tumor suppressor. This becomes the basis for the development of HIF2α-specific antagonists for the treatment of ccRCC.

MSD is currently developing MK-6482, a first-in-class item that intensively targets HIF2α, and clinical trials were conducted (NCT03401788). According to clinical data with 13 months of follow-up, it is noteworthy that the overall response rate (overall response rate) of 24% was drawn from patients who had previously had no treatment response to VEGF inhibitor-type targeted anticancer drugs or immune checkpoint inhibitors. Meanwhile, as another clinical trial for the treatment of ccRCC, the combination therapy of MK-6482 and cabozantinib is being attempted and is expected to be completed in 2022 (NCT03634540).

An object of one aspect of the present invention is to provide a phenylpyrimidine derivative compound.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or treating cancer containing the compound as an active ingredient.

Another object of the present invention is to provide a method for treating cancer comprising administering the compound to a subject in need thereof.

Another object of the present invention is to provide the compound for use in preventing or treating cancer.

Another object of the present invention is to provide a use of the compound for preparing a medicament for use in preventing or treating cancer.

Another object of the present invention is to provide a reagent for inhibiting heteromerization between HIF2α and ARNT in which the compound is selective.

In order to achieve the above purpose,

One aspect of the present invention provides a compound represented by Formula 1 described herein or a pharmaceutically acceptable salt thereof.

In addition, another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.

Furthermore, another aspect of the present invention provides a health functional food composition for preventing or improving cancer containing the compound as an active ingredient.

In addition, another aspect of the present invention provides a method for treating cancer comprising administering the compound to a subject in need thereof.

Furthermore, another aspect of the present invention provides the compound for use in preventing or treating cancer.

In addition, another aspect of the present invention provides a use of the compound for preparing a medicament for use in preventing or treating cancer.

Furthermore, another aspect of the present invention provides a reagent for inhibiting heteromerization between HIF2α and ARNT containing the above compound.

It was found by the present invention that the compound according to the present invention, that is, a pyrimidine derivative or a pharmaceutically acceptable salt thereof, has a selective HIF2α-ARNT heteromerization inhibitory activity. Therefore, the compound according to the present invention, that is, a pyrimidine derivative or a pharmaceutically acceptable salt thereof, can be usefully applied to the prevention or treatment of renal cancer.

Hereinafter, the present invention will be described in detail.

Meanwhile, the embodiments of the present invention may be modified in various forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Furthermore, the inclusion of a certain component in the entire specification means that other components may be further included without excluding other components unless otherwise stated.

One aspect of the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ₁ is hydrogen, halogen, hydroxy, or C _1-5 straight or branched chain alkoxy;

,

,

, 또는

이고;L is methylene;

,

,

, or

ego;

, 또는

이고;R ₂ is hydrogen, -NH ₂ ,

, or

ego;

Wherein A ₁ is C _1-5 straight or branched chain alkyl;

A ₂ and A ₃ are independently hydrogen, C _1-5 straight-chain or branched-chain alkyl, C _1-5 straight-chain or branched-chain alkoxy, phenyl, unsubstituted or substituted C _3-6 cycloalkyl,

The substituent of the substituted C _3-6 cycloalkyl is -CN;

X is -NH- or -O-; and

Ar is unsubstituted, substituted or fused phenyl, or

An unsubstituted or substituted 5-6 membered heteroaryl containing at least one heteroatom selected from the group consisting of N and O;

The substituted phenyl is halogen, -CF ₃ , -CN, -OCF ₃ , C _1-5 straight-chain or branched-chain alkyl, aminosulfonyl, methylsulfonyl, methylamino, dimethylamino, C _1-3 alkylcarbonyl and C _2-5 phenyl substituted with one or more substituents selected from the group consisting of alkenylcarbonylamino;

The fused phenyl is a phenyl fused with a 5-membered heteroaryl containing at least one N,

The substituted 5-6 membered heteroaryl is a C _5-6 heteroaryl in which one or more substituents selected from the group consisting of C _1-5 straight-chain or branched-chain alkyl and -CF ₃ are substituted.

On the other side of things,

R ₁ is hydrogen, fluorine, hydroxy, or methoxy;

,

,

, 또는

이고;L is methylene;

,

,

, or

ego;

, 또는

이고;R ₂ is hydrogen, -NH ₂ ,

, or

ego;

wherein A ₁ is ethyl;

A ₂ and A ₃ are independently hydrogen, methyl, ethyl, methoxy, phenyl, unsubstituted or substituted cyclopropyl,

The substituent of the substituted cyclopropyl is -CN; and

X is -NH- or -O-;

Wherein Ar is unsubstituted, substituted or fused phenyl, or

An unsubstituted or substituted 5-6 membered heteroaryl containing at least one heteroatom selected from the group consisting of N and O;

The substituted phenyl is halogen, -CF ₃ , -CN, -OCF ₃ , methyl, aminosulfonyl, methylsulfonyl, methylamino, dimethylamino, C _1-3 alkylcarbonyl and C ₂ alkenylcarbonylamino A phenyl substituted with one or more substituents selected from the group consisting of

The fused phenyl is a phenyl fused with a 5-membered heteroaryl containing at least one N,

The substituted 5-6 membered heteroaryl is a C _5-6 heteroaryl in which one or more substituents selected from the group consisting of methyl and -CF ₃ are substituted.

On the other side of things,

R ₁ is -H, -F, -OH, or -OCH ₃ ;

,

,

,

,

,

,

,

, 또는

이고,R ₂ is -H;

,

,

,

,

,

,

,

, or

ego,

X is -NH- or -O-;

,

,

, 또는

이고; 및L is methylene;

,

,

, or

ego; and

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, 또는

일 수 있다.Ar is

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

can be

The compound represented by Formula 1 may be any one compound selected from the group of compounds below.

(1) ethyl 1-(2-(phenylamino)pyrimidin-4-yl)cyclohexane-1-carboxylate;

(2) ethyl 1-(2-((3-chlorophenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;

(3) ethyl 1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;

(4) ethyl 1-(2-((4-chloro-3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;

(5) ethyl 1-(2-((4-fluoro-3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;

(6) ethyl 1-(2-((3-fluorophenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;

(7) ethyl 1-(2-((3-chloro-5-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;

(8) ethyl-1-(2-((3-fluorophenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;

(9) ethyl 1-(2-((4-fluoro-3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;

(10) 4-cyclopentyl-N-(3-fluorophenyl)pyrimidin-2-amine;

(11) 4-cyclopentyl-N-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-amine;

(12) 4-cyclohexyl-N-phenylpyrimidin-2-amine;

(13) 3-((4-cyclohexylpyrimidin-2-yl)amino)benzenesulfonamide;

(14) N-(4-chloro-3-(trifluoromethyl)phenyl)-4-cyclohexylpyrimidin-2-amine;

(15) ethyl 1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;

(16) ethyl 1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;

(17) 3-((4-cyclopentylpyrimidin-2-yl)amino)benzenesulfonamide;

(18) 4-((4-cyclopentylpyrimidin-2-yl)amino)benzenesulfonamide;

(19) ethyl 1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;

(20) ethyl 1-(2-((4-acrylamidophenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;

(21) N-(1-cyanocyclopropyl)-1-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(22) N-ethyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(23) N-ethyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(24) 1-(2-((3-acetylphenyl)amino)pyrimidin-4-yl)-N-ethylcyclopentane-1-carboxamide;

(25) 1-(2-((1H-indazol-5-yl))amino)pyrimidin-4-yl)-N-ethylcyclopentane-1-carboxamide;

(26) N-phenyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(27) N-phenyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(28) ethyl 1-(2-((3-acetylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;

(29) ethyl 1-(2-((1H-indazol-5-yl))amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;

(30) ethyl 1-(2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;

(31) ethyl 1-(2-((3-cyano-5-fluorophenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;

(32) N-methoxy-N-methyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(33) N-methyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(34) N-methyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide;

(35) N-methyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide;

(36) N-methyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(37) 1-(2-((3-acetylphenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(38) N-methyl-1-(2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(39) N-methyl-1-(2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(40) 1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(41) 4-((4-(1-aminocyclohexyl)pyrimidin-2-yl)amino)benzenesulfonamide;

(42) 1-(2-((4-(dimethylamino)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(43) 1-(2-((3-fluoro-4-sulfamoylphenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(44) N-methyl-1-(2-(4-sulfamoylphenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(45) N-methyl-1-(2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(46) 1-(5-fluoro-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(47) 1-(5-methoxy-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(48) 3-((4-(1-aminocyclohexyl)pyrimidin-2-yl)amino)benzenesulfonamide;

(49) 4-(1-aminocyclohexyl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine;

(50) 4-((4-(1-aminocyclohexyl)pyrimidin-2-yl)oxy)benzenesulfonamide;

(51) N-methyl-1-(2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(52) N-methyl-1-(2-(4-(methylsulfonyl)phenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide;

(53) 1-(5-hydroxy-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide;

(54) 1-(2-(3-cyanophenoxy)-5-methoxypyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide;

(55) 1-(5-methoxy-2-(4-(trifluoromethoxy)phenoxy)pyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide;

(56) 1-(2-(3-cyanophenoxy)pyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide;

(57) N,2-dimethyl-2-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)propanamide;

(58) N,2-dimethyl-2-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)propanamide;

(59) N,2-dimethyl-2-(2-((4-sulfamoylphenoxy)pyrimidin-4-yl)propanamide;

(60) 2-(5-methoxy-2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(61) 1-(5-methoxy-2-(3-(methylsulfonyl-phenoxy)pyrimidin-4-yl)-N-methylcyclopropane-1-carboxamide;

(62) 1-(2-((3-cyano-5-fluorophenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopropane-1-carboxamide;

(63) 1-(2-((4-fluoro-3-(trifluoromenyl)phenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopropane-1-carbox amides;

(64) 1-(5-methoxy-2-((2-methylpyridin-4-yl)oxy)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(65) 1-(5-methoxy-2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(66) 1-(5-methoxy-2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(67) 2-(5-methoxy-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(68) 2-(5-methoxy-2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(69) 2-(5-methoxy-2-((4-methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(70) 1-(5-methoxy-2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(71) 1-(5-methoxy-2-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide ;

(72) 1-(5-methoxy-2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopropane-1-carboxamide;

(73) 1-(2-((3-cyanophenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(74) 1-(2-((2-fluoro-5-methylphenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;

(75) 2-(5-methoxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(76) 2-(5-methoxy-2-(4-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(77) N,2-dimethyl-2-(2-(3-sulfamoylphenoxy)pyrimidin-4-yl)propanamide;

(78) N,2-dimethyl-2-(2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)propanamide;

(79) 2-(5-methoxy-2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(80) 2-(5-methoxy-2-((2-(methylpyridin-4-yl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(81) 2-(5-methoxy-2-((2-(methylpyridin-4-yl)oxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(82) N,2-dimethyl-2-(2-((2-methylpyridin-4-yl)oxy)pyrimidin-4-yl)propanamide;

(83) 2-(2-(3-cyanophenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(84) 2-(5-methoxy-2-((3-(sulfamoylphenyl)amino)pyrimidin-4-yl)-N,N,2-trimethylpropanamide;

(85) 2-(5-methoxy-2-((4-(sulfamoylphenyl)amino)pyrimidin-4-yl)-N,N,2-trimethylpropanamide;

(86) 2-(5-methoxy-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,N,2-trimethylpropanamide;

(87) 2-(5-methoxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,N,2-trimethylpropanamide;

(88) 2-(2-((3,4-dimethylisoxazol-5-yl)amino)-5-methoxypyrimidin-4-yl)-N,2-dimethylpropanamide;

(89) 2-(5-fluoro-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(90) 2-(5-methoxy-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(91) 2-(5-hydroxy-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(92) 2-(5-hydroxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(93) 2-(5-methoxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)propan-2-amine;

(94) 3-((4-(2-aminopropan-2-yl)-5-methoxypyrimidin-2-yl)oxy)benzenesulfonamide;

(95) 2-(5-methoxy-2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)propan-2-amine;

(96) 2-(5-methoxy-2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;

(97) 3-((4-(2-aminopropan-2-yl)-5-fluoropyrimidin-2-yl)oxy)benzenesulfonamide; and

(98) 2-(5-fluoro-2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)propan-2-amine.

The compound of Formula 1 of the present invention may be in the form of a pharmaceutically acceptable salt. The salts include common acid addition salts, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and salts derived from inorganic acids such as citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, and salts derived from organic acids such as benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid or aspartic acid. In addition, the salt is in the form of a common metal salt, for example, an alkali metal salt such as lithium, sodium, or potassium; alkaline earth metal salts such as calcium or magnesium salts; or a chromium salt. It also includes salts formed with suitable organic ligands, for example, quaternary ammonium salts, dicyclohexylamine or N-methyl-D-glucamine salts, and amino acid salts formed with arginine, lysine, and the like.

In addition, the present invention provides a method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof. For example, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be prepared according to Reaction Scheme 1 below.

<Scheme 1>

In Scheme 1, R ₁ , R ₂ , X, L, and Ar are as defined above.

In Scheme 1, the starting materials 2,4-dichloropyrimidine derivative and ethyl malonate are commercially available,

In Reaction Scheme 1, the reaction between the 2,4-dichloropyrimidine derivative and ethyl malonate to prepare the compound of Formula 2 may be carried out in the presence of a base such as sodium hydride. In addition, the reaction may be carried out in the presence of at least one solvent selected from the group consisting of tetrahydrofuran and toluene. The reaction may be carried out, for example, at the reflux temperature of the solvent used, but is not limited thereto.

The compound of Formula 3 can be obtained by reacting the compound of Formula 2 with various dihalogenalkyl compounds. The reaction between the compound of Formula 2 and dihalogenalkyl may be carried out in the presence of a base such as sodium hydride, and the reaction may be performed in the presence of at least one solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, and toluene. The reaction may be carried out at a temperature of 20 to 80 °C, preferably 50 to 70 °C.

The compound of Formula 4 can be obtained by reacting the compound of Formula 3 with various alkylamines after hydrolysis. The hydrolysis may be performed by reacting sodium hydroxide, potassium hydroxide, and the like with the compound of Formula 3. Also, the hydrolysis may be carried out in water and an alcohol such as ethanol. Reagents such as hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) and bases such as N, N'-diisopropylethylamine (DIEA) for the production of the hydrolysis product and active esters of various carboxylic acids can be performed under The reaction may be carried out in the presence of a solvent selected from the group consisting of dichloromethane, tetrahydrofuran, and toluene. The reaction may be carried out at a temperature of 20 to 80 °C.

The compound of Formula 1 can be obtained by reacting the compound of Formula 4 with various amine and alcohol compounds.

Buchwald-Hatwig amination reaction using the compound of formula 4 and various amine compounds and palladium (Pd) catalytic bonding or various alcohol compounds and potassium carbonate (K ₂ CO ₃ ) Conducted in the presence of a base such as It can be. In addition, the reaction may be carried out in the presence of one or more solvents selected from the group consisting of N,N'-dimethylformamide, dimethyl sulfoxide, and toluene. The reaction may be carried out at a temperature of 80 to 130 °C.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The cancer is, for example, a cancer related to heteromerization between HIF2α and ARNT, and the compound represented by Chemical Formula 1 according to the present invention inhibits heteromerization between HIF2α and ARNT to prevent or treat cancer. Preferably the cancer is renal cancer.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered to a patient in a therapeutically effective amount, wherein the therapeutically effective amount refers to an amount sufficient to achieve cancer prevention or treatment. The therapeutically effective amount range may vary depending on the patient's age, body weight, sensitivity, symptoms or efficacy of the compound.

The pharmaceutical composition may include a pharmaceutically acceptable carrier such as commonly used excipients, disintegrants, sweeteners, lubricants, or flavoring agents, and tablets, capsules, powders, granules, and suspensions according to conventional methods. , oral preparations such as emulsions or syrups; Alternatively, it may be formulated into a preparation for parenteral administration such as an injection. The formulation may be formulated in a variety of forms, for example single dose or multiple dose dosage forms.

The pharmaceutical composition of the present invention may include excipients such as lactose and corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and tonicity agents. If desired, sweetening and/or flavoring agents may be added.

The composition of the present invention may be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. Accordingly, the composition of the present invention may be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of tablets for oral use, carriers such as lactose and corn starch and lubricants such as magnesium stearate may usually be added. In the case of capsules for oral administration, lactose and/or dried corn starch may be used as diluents. When oral aqueous suspensions are required, the active ingredient may be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredients are usually prepared, the pH of the solutions suitably adjusted and buffered. For intravenous administration, the total concentration of solutes should be adjusted to impart isotonicity to the formulation. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4. The solution can be introduced into the patient's intramuscular bloodstream by local bolus injection.

In addition, the present invention also provides a reagent for inhibiting heteromerization between HIF2α and ARNT, including the compound of Formula 1 or a salt thereof.

Hereinafter, the present invention will be described in detail through preparation examples, examples, and experimental examples.

However, preparation examples, examples, and experimental examples to be described later are only to specifically illustrate the present invention in one aspect, but the present invention is not limited thereto.

<Preparation Example 1> Preparation of N,2-dimethyl-2-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)propanamide

Step 1: Synthesis of diethyl 2-(2-chloropyrimidin-4-yl)malonate

Diethylmalonate (4 g, 1.5 eq) was stirred with sodium hydride (NaH) (2 g, 3 eq) in a solvent of 200 mL of tetrahydrofuran (THF) at 0 °C for 30 minutes. After adding 2,4-dichloropyrimidine (2.5 g) dropwise, the mixture was heated under reflux at 70 °C for 3 hours. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was dried using magnesium sulfate and distilled under reduced pressure. The resulting residue was purified by column chromatography (MPLC) to obtain the title compound (3.7 g, 80%).

[M+1] ⁺ = 273.20

Step 2: Synthesis of ethyl 2-(2-chloropyrimidin-4-yl)acetate

Diethyl 2-(2-chloropyrimidin-4-yl)malonate (2 g) and sodium ethoxide (NaOEt) (0.1 eq) obtained in step 1 were heated to reflux for 3 hours in an ethanol solvent. The reaction was complete. After neutralization using 1M HCl at 0 ℃ to pH 7, the reaction mixture was extracted using ethyl acetate and water, and the organic layer was dried using magnesium sulfate and distilled under reduced pressure. The resulting residue was purified by column chromatography (MPLC) to obtain the title compound (660 mg, 45%).

[M+H] ⁺ = 201.30

Step 3: Synthesis of ethyl 2-(2-chloropyrimidin-4-yl)-2-methylpropanoate

Ethyl 2- (2-chloropyrimidin-4-yl) acetate (1.2 g) obtained in step 2 was mixed with sodium hydride (NaH) (710 mg, 3e q) in 50 mL of tetrahydrofuran (THF) as a solvent at 0 ° C. stirred for 30 minutes. Thereafter, methyl iodine (MeI) (3.4 g, 4 eq) was added dropwise and reacted at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was dried using magnesium sulfate and distilled under reduced pressure. The obtained residue was purified by column chromatography (MPLC) to obtain the title compound (875 mg, 65%).

[M+H] ⁺ = 229.2

Step 4: Synthesis of 2-(2-chloropyrimidin-4-yl)-N,2-dimethylpropanamide

Ethyl 2-(2-chloropyrimidin-4-yl)-2-methylpropanoate (700 mg) obtained in step 3 was mixed with 2M sodium hydroxide (NaOH) (9mL, 3 eq) in 9mL ethanol solvent at 70 °C. After hydrolysis by stirring, the reaction mixture was extracted using ethyl acetate and water, and the organic layer was dried using magnesium sulfate and distilled under reduced pressure, and the reaction mixture was dichloromethane (CH ₂ Cl ₂ ) without further purification under HATU as a solvent. After adding DIEA dropwise and stirring at room temperature for 30 minutes, 2M methylamine (3.6 mL, 2 eq) was added dropwise and reacted for 5 hours. After completion of the reaction, extraction was performed using dichloromethane and water, and the organic layer was dried using magnesium sulfate and distilled under reduced pressure. The resulting residue was purified by column chromatography (MPLC) to obtain the title compound (470 mg, 72%).

[M+H] ⁺ = 214.30

Step 5: Synthesis of N,2-dimethyl-2-(2-((3-sulfamoylphenyl)amino)pyrimidin-4yl)propanamide

2-(2-chloropyrimidin-4-yl)-N,2-dimethylpropanamide (45 mg) obtained in step 4 was mixed with 3-aminobenzenesulfonamide (72.6 mg, 2 eq) and tris(dimethylpropanamide) in toluene solvent. Benzylideneacetone) dipalladium (0) (Pd ₂ dba ₃ ) (5 mg, 0.1 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (12 mg, 0.1 eq), and cesium carbonate (Cs ₂ CO ₃ ) (38 mg, 3 eq) were added and then stirred in a microwave reactor at 120 °C for 2 hours, and the reaction mixture was extracted with ethyl acetate and water. , The organic layer was dried using magnesium sulfate, and the residue obtained by distillation under reduced pressure was purified by reverse phase column chromatography (Prep-HPLC) to obtain the title compound (30 mg, 41%).

[M+H] ⁺ = 350.5

Hereinafter, the compounds of Examples 1 to 98 of the present invention were prepared with reference to the above Preparation Examples.

<Example 1> Ethyl 1-(2-(phenylamino)pyrimidin-4-yl)cyclohexane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.34 (d, J = 5.3 Hz, 1H), 7.67–7.60 (m, 2H), 7.37–7.30 (m, 2H), 7.10 (s, 1H), 7.05–6.99 (m, 1H), 6.73 (d, J = 5.2 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.37 (d, J = 13.3 Hz, 2H), 1.94–1.80 (m, 2H), 1.75–1.60 (m, 3H), 1.55–1.44 (m, 2H), 1.38–1.27 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H).

LCMS (ESI): Exact mass calcd for C ₁₉ H ₂₃ N ₃ O ₂ [M+H] ⁺ 325.18, found 326.15.

<Example 2> Ethyl 1-(2-((3-chlorophenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.37 (d, J = 5.2 Hz, 1H), 7.92 (t, J = 2.1 Hz, 1H), 7.38 (ddd, J = 8.3, 2.2, 0.9 Hz, 1H), 7.23 (t, J = 8.1 Hz, 1H) ), 7.18 (br. s, 1H), 6.99 (ddd, J = 7.9, 2.1, 0.9 Hz, 1H), 6.78 (d, J = 5.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H) , 2.42-2.31 (m, 2H), 1.96-1.83 (m, 2H), 1.75-1.62 (m, 3H), 1.59-1.44 (m, 2H), 1.41-1.28 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H).

LCMS (ESI): Exact mass calcd for C ₁₉ H ₂₂ ClN ₃ O ₂ [M+H] ⁺ 359.14, found 360.10.

<Example 3> Ethyl 1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.81 (t, J = 2.0 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.59 (dt, J = 7.7, 1.3 Hz, 1H), 7.45 (br. s, 1H), 7.39 (t , J = 7.9 Hz, 1H), 7.23 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 5.68 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 2.44 (d, J = 12.1 Hz, 2H), 1.77-1.65 (m, 5H), 1.58-1.44 (m, 2H), 1.35-1.27 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H).

LCMS (ESI): Exact mass calcd for C ₁₉ H ₂₄ N ₄ O ₄ S [M+H] ⁺ 404.15, found 405.05.

<Example 4> Ethyl 1-(2-((4-chloro-3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.38 (d, J = 5.3 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 7.70 (dd, J = 8.8, 2.7 Hz, 1H), 7.42 (d, J =8.7 Hz, 1H), 7.35 (s, 1H), 6.82 (d, J = 5.3 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 2.42-2.32 (m, 2H), 1.97-1.83 (m, 2H), 1.72 −1.62 (m, 3H), 1.58–1.46 (m, 2H), 1.40–1.29 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H).

LCMS (ESI): Exact mass calcd for C ₂₀ H ₂₁ ClF ₃ N ₃ O ₂ [M+H] ⁺ 427.13, found 428.05.

<Example 5> Ethyl 1-(2-((4-fluoro-3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.36 (d, J = 5.2 Hz, 1H), 8.12 (dd, J = 6.3, 2.8 Hz, 1H), 7.68 (dt, J = 8.9, 3.5 Hz, 1H), 7.35 (br. s, 1H), 7.15 (t, J = 9.4 Hz, 1H), 6.80 (d, J = 5.3 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 2.42–2.31 (m, 2H), 1.96–1.83 (m, 2H), 1.71–1.58 (m, 3H), 1.58–1.46 (m, 2H), 1.40–1.27 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H).

LCMS (ESI): Exact mass calcd for C ₂₀ H ₂₁ F ₄ N ₃ O ₂ [M+H] ⁺ 411.16, found 412.20.

<Example 6> Ethyl 1-(2-((3-fluorophenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.37 (d, J = 5.2 Hz, 1H), 7.77 (dt, J = 11.8, 2.3 Hz, 1H), 7.43 (br. s, 1H), 7.29–7.20 (m, 1H), 7.17 (ddd, J = 8.2, 2.1, 1.1 Hz, 1H), 6.78 (d, J = 5.3 Hz, 1H), 6.70 (tdd, J = 8.2, 2.6, 1.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.44-2.34 (m, 2H), 1.92-1.82 (m, 2H), 1.76-1.59 (m, 3H), 1.59-1.46 (m, 2H), 1.42-1.27 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H).

LCMS (ESI): Exact mass calcd for C ₁₉ H ₂₂ FN ₃ O ₂ [M+H] ⁺ 343.17, found 344.90

<Example 7> Ethyl 1-(2-((3-chloro-5-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.40 (d, J = 5.3 Hz, 1H), 7.94 (dt, J = 9.3, 1.9 Hz, 2H), 7.66 (s, 1H), 7.24 (d, J = 1.7 Hz, 1H), 6.85 (d, J = 5.3 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.44–2.31 (m, 2H), 2.02–1.87 (m, 2H), 1.71–1.46 (m, 5H), 1.42–1.28 ( m, 1H), 1.21 (t, J = 7.1 Hz, 3H).

LCMS (ESI): Exact mass calcd for C ₂₀ H ₂₁ ClF ₃ N ₃ O ₂ [M+H] ⁺ 427.13, found 428.10

<Example 8> Ethyl 1-(2-((3-fluorophenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.35 (d, J = 5.2 Hz, 1H), 8.11 (dd, J = 6.2, 2.8 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.21 (s, 1H), 7.24 (t, J = 9.4 Hz) , 1H), 6.75 (d, J = 5.2 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.49–2.43 (m, 2H), 2.22–2.15 (m, 2H), 1.78–1.71 ( m, 4H), 1.19 (t, J = 7.1 Hz, 3H).

LCMS (ESI): Exact mass calcd for C ₁₈ H ₂₀ FN ₃ O ₂ [M+H] ⁺ 329.15, found 330.10

<Example 9> Ethyl 1-(2-((4-fluoro-3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.36 (d, J = 5.3 Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 8.7, 2.6 Hz, 1H), 7.58 (bs, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.26 (s, 1H), 6.79 (d, J = 5.3 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.50–2.44 (m, 2H), 2.22–2.15 (m, 2H), 1.79–1.73 (m, 4H), 1.19 (t, J = 7.1 Hz, 3H).

LCMS (ESI): Exact mass calcd for C19H19F4N3O2 [M+H] ⁺ 397.14, found 398.15

<Example 10> 4-cyclopentyl-N-(3-fluorophenyl)pyrimidin-2-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.28 (d, J = 5.1 Hz, 1H), 8.19 (dd, J = 6.2, 2.7 Hz, 1H), 7.65 - 7.62 (m, 1H), 7.16 (s, 1H), 7.24 (t, J = 9.5 Hz) , 1H), 6.68 (d, J = 5.1 Hz, 1H), 3.07 - 3.04 (m, 1H), 2.09 - 2.02 (m, 2H), 1.85 - 1.72 (m, 4H), 1.71 - 1.59 (m, 2H) ).

LCMS (ESI): Exact mass calcd for C ₁₅ H ₁₆ FN ₃ [M+H] ⁺ 257.13, found 258.10

<Example 11> 4-cyclopentyl-N-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ ; 8.28 (d, J = 5.2 Hz, 1H), 7.98 (m, 1H), 7.65 - 7.62 (m, 1H), 7.18 (m, 1H), 6.68 (d, J = 5.1 Hz, 1H), 3.09 - 3.06 (m, 1H), 2.12-2.05 (m, 2H), 1.88-1.75 (m, 4H), 1.74 - 1.61 (m, 2H).

LCMS (ESI): Exact mass calcd for C16H15F4N3 [M+H] ⁺ 325.12, found 326.15.

<Example 12> 4-cyclohexyl-N-phenylpyrimidin-2-amine

¹ H NMR (400 MHz, Methanol- d ₄ ) δ; 8.27 (d, J = 5.2 Hz, 1H), 7.75–7.65 (m, 2H), 7.35–7.23 (m, 2H), 6.99 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 5.2 Hz) , 1H), 2.65-2.49 (m, 1H), 1.99-1.92 (m, 2H), 1.92-1.85 (m, 2H), 1.82-1.73 (m, 1H), 1.66-1.52 (m, 2H), 1.52 -1.38 (m, 2H), 1.38-1.24 (m, 2H).

LCMS (ESI): Exact mass calcd for C ₁₆ H ₁₉ N ₃ [M+H] ⁺ 253.16, found 254.15

<Example 13> 3-((4-cyclofexylpyrimidin-2-yl)amino)benzenesulfonamide

¹ H NMR (400 MHz, Methanol- d ₄ ) δ; 8.27 (d, J = 5.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.8 Hz, 2H), 6.99 (t, J = 7.4 Hz, 1H), 6.68 ( d, J = 5.1 Hz, 1H), 2.65–2.49 (m, 1H), 2.02–1.92 (m, 2H), 1.92–1.84 (m, 2H), 1.83–1.74 (m, 1H), 1.66–1.52 ( m, 2H), 1.52–1.39 (m, 2H), 1.38–1.26 (m, 1H).

LCMS (ESI): Exact mass calcd for C ₁₆ H ₂₀ N ₄ O ₂ S [M+H] ⁺ 332.13, found 333.15.

<Example 14> N-(4-chloro-3-(trifluoromethyl)phenyl)-4-cyclohexylpyrimidin-2-amine

¹ H NMR (400 MHz, Methanol- d ₄ ) δ; 8.47 (d, J = 2.6 Hz, 1H), 8.23 (d, J = 5.1 Hz, 1H), 7.70 (dd, J = 8.8, 2.6 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 5.1 Hz, 1H), 2.58-2.44 (m, 1H), 1.89-1.82 (m, 2H), 1.82-1.74 (m, 2H), 1.72-1.65 (m, 1H), 1.57- 1.45 (m, 2H), 1.41–1.28 (m, 2H), 1.27–1.16 (m, 1H).

LCMS (ESI): Exact mass calcd for C ₁₇ H ₁₇ ClF ₃ N ₃ [M+H] ⁺ 355.11, found 356.20.

<Example 15> Ethyl 1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.93 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.33 (t, J = 1.8 Hz, 1H), 7.94 (dd, J = 8.0, 2.1 Hz, 1H), 7.48 - 7.39 (m , 2H), 7.28 (S, 2H), 6.86 (d, J = 5.2 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.37 - 2.31 (m, 2H), 2.21 - 2.14 (m, 2H), 1.70 - 1.65 (m, 4H), 1.11 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₁₈ H ₂₂ N ₄ O ₄ S [M+H] ⁺ 390.14, found 391.15.

<Example 16> Ethyl 1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.0 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.17 (S, 2H), 6.92 (d, J = 5.2 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 2.39 - 2.32 (m, 2H), 2.17 - 2.11 (m, 2H), 1.72 - 1.66 (m, 4H) , 1.11 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₁₈ H ₂₂ N ₄ O ₄ S [M+H] ⁺ 390.14, found 391.15.

<Example 17> 3-((4-cyclopentylpyrimidin-2-yl)amino)benzenesulfonamide

¹ H NMR (400 MHz, Methanol- d ₄ ) δ; 8.40 (s, 1H), 8.23 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 6.73 (d, J = 5.2 Hz, 1H), 3.07 - 3.03 (m, 1H), 2.02 - 1.98 (m, 2H), 1.83 - 1.79 (m, 4H), 1.69 - 1.61 (m, 2H).

LCMS (ESI): Exact mass calcd for C ₁₅ H ₁₈ N ₄ O ₂ S [M+H] ⁺ 318.12, found 319.10

<Example 18> 4-((4-cyclopentylpyrimidin-2-yl)amino)benzenesulfonamide

¹ H NMR (400 MHz, Methanol- d ₄ ) δ; 8.28 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 6.72 (d, J = 5.2 Hz, 1H), 3.09 - 3.01 (m, 1H), 1.99 - 1.93 (m, 2H), 1.81 - 1.72 (m, 4H), 1.69 - 1.64 (m, 2H).

LCMS (ESI): Exact mass calcd for C ₁₅ H ₁₈ N ₄ O ₂ S [M+H] ⁺ 318.12, found 319.10

<Example 19> Ethyl 1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ; 10.8 (bs, 1H), 8.28 (d, J = 6.0 Hz, 1H), 7.94 - 7.89 (m, 4H), 7.00 (d, J = 6.0 Hz, 1H), 4.78 (bs, 2H), 4.20 (q , J = 7.1 Hz, 2H), 2.43 - 2.40 (m, 2H), 1.90 - 1.84 (m, 2H), 1.71 - 1.68 (m, 3H), 1.60 - 1.54 (m, 2H), 1.36 - 1.33 (m , 1H), 1.22 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₁₉ H ₂₄ N ₄ O ₄ S [M+H] ⁺ 404.15, found 405.15

<Example 20> Ethyl 1-(2-((4-acrylamidophenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate

LRMS(ESI): m/z = [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ; 8.28 (d, J = 5.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.29 (s, 1H), 6.70 (d, J = 5.4 Hz, 1H), 6.43 (d, J = 16.7 Hz, 1H), 6.27 - 6.21 (m, 1H), 5.76 (d, J = 10.2 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 2.46 - 2.43 (m, 2H), 2.21 - 2.15 (m, 2H), 1.77 - 1.74 (m, 4H), 1.19 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₂₁ H ₂₄ N ₄ O ₃ [M+H] ⁺ 380.18, found 381.20

<Example 21> N-(1-cyanocyclopropyl)-1-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ; 9.1 (bs, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.25 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 5.5 Hz, 1H), 6.63 (s, 1H), 2.48 - 2.42 (m, 2H), 2.21 - 2.18 (m, 2H), 1.82 - 1.78 (m, 2H), 1.76 - 1.72 (m, 2H), 1.46 (t, J = 5.7 Hz, 2H), 1.03 (t, J = 5.8 Hz, 2H).

LCMS (ESI): Exact mass calcd for C21H20F3N5O [M+H] ⁺ 415.16, found 416.20

<Example 22> N-ethyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.0 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.56 (S, 1H), 7.19 (s, 2H), 6.84 (d, J = 5.2 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 2.33 - 2.28 (m, 2H), 2.14 - 2.08 (m, 2H), 1.65 - 1.60 (m, 4H), 0.95 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₁₈ H ₂₃ N ₅ O ₃ S [M+H] ⁺ 389.15, found 390.15.

<Example 23> N-ethyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.92 (s, 1H), 8.44 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.52 (t, J = 5.6 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H) 7.39 (d, J = 7.8 Hz, 1H), 7.33 (s, 2H), 6.81 (d, J = 5.2 Hz, 1H), 3.06 (q, J = 7.1 Hz) , 2H), 2.33 - 2.30 (m, 2H), 2.15 - 2.11 (m, 2H), 1.65 - 1.60 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₁₈ H ₂₃ N ₅ O ₃ S [M+H] ⁺ 389.15, found 390.15.

<Example 24> 1-(2-((3-acetylphenyl)amino)pyrimidin-4-yl)-N-ethylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.78 (s, 1H), 8.48 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 5.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 5.1 Hz, 1H), 3.06 (q, J = 7.1 Hz, 2H), 2.58 ( s, 3H), 2.34 - 2.29 (m, 2H), 2.17 - 2.12 (m, 2H), 1.64 - 1.60 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₂₀ H ₂₄ N ₄ O ₂ [M+H] ⁺ 352.19, found 353.20.

<Example 25> 1-(2-((1H-indazol-5-yl))amino)pyrimidin-4-yl)-N-ethylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.51 (s, 1H), 8.36 (d, J = 5.2 Hz, 1H), 8.29 (s, 1H), 7.96 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 5.5 Hz, 1H) 7.44 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 5.2 Hz, 1H), 3.07 (q, J = 7.1 Hz, 2H), 2.33 - 2.26 (m, 2H) , 2.17 - 2.12 (m, 2H), 1.66 - 1.60 (m, 4H), 0.94 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₁₉ H ₂₂ N ₆ O [M+H] ⁺ 350.19, found 351.20.

<Example 26> N-phenyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.98 (s, 1H), 9.35 (s, 1H), 8.42 (d, J = 5.1 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.21 (t, J = 7.8 Hz, 2H), 7.11 (s, 2H), 6.96 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 5.2 Hz, 1H), 2.43 - 2.39 (m, 2H), 2.15 - 2.10 (m, 2H), 1.68 - 1.61 (m, 4H).

LCMS (ESI): Exact mass calcd for C ₂₂ H ₂₃ N ₅ O ₃ S [M+H] ⁺ 437.15, found 438.15.

<Example 27> N-phenyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.91 (s, 1H), 9.35 (s, 1H), 8.39 (d, J = 5.1 Hz, 1H), 8.24 (s, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.32 - 7.18 (m, 6H), 6.96 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 5.2 Hz, 1H), 2.43 - 2.38 (m, 2H), 2.16 - 2.10 (m, 2H), 1.68 - 1.60 (m, 4H).

LCMS (ESI): Exact mass calcd for C ₂₂ H ₂₃ N ₅ O ₃ S [M+H] ⁺ 437.15, found 438.15.

<Example 28> Ethyl 1-(2-((3-acetylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.80 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.41 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 5.1 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H), 2.37 - 2.30 (m, 2H) ), 2.20 - 2.15 (m, 2H), 1.71 - 1.64 (m, 4H), 1.09 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₂₀ H ₂₃ N ₃ O ₃ [M+H] ⁺ 353.17, found 354.15.

<Example 29> Ethyl 1-(2-((1H-indazol-5-yl))amino)pyrimidin-4-yl)cyclopentane-1-carboxylate

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.55 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.58 (dd, J = 9.0, 1.6 Hz, 1H), 7.45 (d , J = 8.9 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 2.37 - 2.31 (m, 2H), 2.19 - 2.08 (m, 2H) , 1.70 - 1.66 (m, 4H), 1.11 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₁₉ H ₂₁ N ₅ O ₂ [M+H] ⁺ 351.17, found 352.15.

<Example 30> Ethyl 1-(2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.53 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 6.96 (d, J = 5.2 Hz, 1H), 4.11 ( q, J = 7.1 Hz, 2H), 2.39 - 2.33 (m, 2H), 2.18 - 2.08 (m, 2H), 1.73 - 1.66 (m, 4H), 1.11 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₁₉ H ₂₃ N ₃ O ₄ S [M+H] ⁺ 389.14, found 390.15.

<Example 31> Ethyl 1-(2-((3-cyano-5-fluorophenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.55 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 8.02 (s, 1H), 7.37 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 5.2 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 2.38 - 2.34 (m, 2H), 2.14 - 2.08 (m, 2H), 1.73 - 1.66 (m, 4H), 1.10 (t, J = 7.1 Hz, 3H),

LCMS (ESI): Exact mass calcd for C ₁₉ H ₁₉ FN ₄ O ₂ [M+H] ⁺ 354.15, found 355.15.

<Example 32> N-methoxy-N-methyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.98 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 7.1 Hz, 2H), 7.68 (d, J = 7.1 Hz, 2H), 7.15 (s, 2H), 6.78 (d, J = 5.2 Hz, 1H), 3.14 (s, 1H), 3.07 (s, 1H), 2.28 - 2.23 (m, 2H), 2.11 - 2.08 (m, 2H), 1.69 - 1.66 (m, 4H).

LRMS(ESI): Exact mass calcd for C18H23N5O4S [M+H] ⁺ 405.15, found 406.15.

<Example 33> N-methyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.98 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 7.1 Hz, 2H), 7.72 (d, J = 7.1 Hz, 2H), 7.45 (m, 1H), 7.15 (s, 2H), 6.85 (d, J = 5.2 Hz, 1H), 2.56 (d, J = 5.2 Hz, 3H), 2.34 - 2.29 (m, 2H), 2.22 - 2.09 (m, 2H), 1.64 - 1.61 (m, 4H).

LRMS(ESI): Exact mass calcd for C17H21N5O3S [M+H] ⁺ 375.14, found 376.15.

<Example 34> N-methyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ; 9.98 (bs, 1H), 8.31 (d, J = 6.0 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 5.8 Hz, 1H), 5.90 (bs, 1H), 4.80 (bs, 2H), 2.78 (d, J = 4.8 Hz, 3H), 2.25 - 2.21 (m, 2H), 2.17 - 2.11 (m, 2H), 1.69 - 1.62 (m, 2H), 1.60 - 1.55 (m, 6H).

LCMS (ESI): Exact mass calcd for C18H23N5O3S [M+H] ⁺ 389.15, found 390.15

<Example 35> N-methyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide

¹ H NMR (400 MHz, MeOD) δ; 8.59 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.33 (m, 2H), 6.82 (d, J = 5.4 Hz, 1H), 2.62 (s, 3H), 2.24 - 2.20 (m, 2H), 1.98 - 1.93 (m, 2H), 1.50 - 1.46 (m, 6H).

LCMS (ESI): Exact mass calcd for C18H23N5O3S [M+H] ⁺ 389.15, found 390.15

<Example 36> N-methyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, MeOD) δ; 8.51 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.37 (m, 2H), 6.80 (d, J = 5.3 Hz, 1H), 2.61 (s, 3H), 2.33 - 2.27 (m, 2H), 2.20 - 2.14 (m, 2H), 1.68 - 1.62 (m, 4H).

LCMS (ESI): Exact mass calcd for C17H21N5O3S [M+H] ⁺ 375.14, found 376.15.

<Example 37> 1-(2-((3-acetylphenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.80 (s, 1H), 8.47 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H) ), 7.46 - 7.41 (m, 2H), 6.79 (d, J = 5.2 Hz, 1H), 2.58 (s, 3H), 2.56 (d, J = 4.5 Hz, 3H), 2.33 - 2.27 (m, 2H) , 2.20 - 2.14 (m, 2H), 1.63 - 1.60 (m, 4H).

LCMS (ESI): Exact mass calcd for C19H22N4O2 [M+H] ⁺ 338.17, found 339.15.

<Example 38> N-methyl-1-(2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.03 (s, 1H), 8.57 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.48 - 7.43 (m, 2H), 6.83 (d, J = 5.2 Hz, 1H), 3.20 (s, 3H), 2.56 (d, J = 4.5 Hz, 3H), 2.33 - 2.28 (m, 2H), 2.19 - 2.12 (m, 2H), 1.63 - 1.60 (m, 4H).

LCMS (ESI): Exact mass calcd for C18H22N4O3S [M+H] ⁺ 374.14, found 375.15.

<Example 39> N-methyl-1-(2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.15 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.51 (bs, 1H), 6.89 (d, J = 5.2 Hz, 1H), 3.16 (s, 3H), 2.56 (d, J = 4.5 Hz, 3H), 2.33 - 2.29 (m, 2H), 2.15 - 2.07 (m, 2H), 1.65 - 1.61 (m, 4H).

LCMS (ESI): Exact mass calcd for C18H22N4O3S [M+H] ⁺ 374.14, found 375.15.

<Example 40> 1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.96 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.17 (s, 2H), 6.86 (d, J = 5.1 Hz, 1H), 2.04 - 1.99 (m, 2H), 1.80 - 1.77 (m, 4H), 1.68 - 1.65 (m, 2H).

LCMS (ESI): Exact mass calcd for C16H19N5O3S [M+H] ⁺ 361.12, found 362.15.

<Example 41> 4-((4-(1-aminocyclohexyl)pyrimidin-2-yl)amino)benzenesulfonamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.19 (s, 1H), 8.67 (d, J = 5.2 Hz, 1H), 8.29 (bs, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 1H), 7.23 (s, 2H), 6.21 (d, J = 5.2 Hz, 1H), 2.25 - 2.22 (m, 2H), 1.84 - 1.82 (m, 2H), 1.54 - 1.52 (m, 2H), 1.46 - 1.44 ( m, 4H).

LCMS (ESI): Exact mass calcd for C16H21N5O2S [M+H] ⁺ 347.14, found 348.15.

<Example 42> 1-(2-((4-(dimethylamino)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.70 (bs, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.81 (bs, 2H), 7.46 - 7.45 (m, 1H), 9.70 (bs, 1H), 6.78 (d, J = 4.8 Hz) , 1H), 3.07 (s, 6H), 2.56 (d, J = 4.5 Hz, 3H), 2.33 - 2.27 (m, 2H), 2.14 - 2.07 (m, 2H), 1.62 - 1.59 (m, 4H).

LCMS (ESI): Exact mass calcd for C19H25N5O [M+H] ⁺ 339.21, found 340.20.

<Example 43> 1-(2-((3-fluoro-4-sulfamoylphenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.05 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.97 (dd, J = 13.8, 1.8 Hz, 1H), 7.59 (t, J = 8.6 Hz, 1H), 7.51 (d, J = 8.8, 1.8 Hz, 2H), 7.43 -7.40 (m, 3H), 6.84 (d, J = 5.2 Hz, 1H), 2.56 (d, J = 4.5 Hz, 3H), 2.27 - 2.24 (m, 2H) , 2.06 - 2.02 (m, 2H), 1.59 - 1.55 (m, 4H).

LRMS(ESI): Exact mass calcd for C17H20FN5O3S [M+H] ⁺ 393.13, found 394.15.

<Example 44> N-methyl-1-(2-(4-sulfamoylphenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.54 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.46 (m, 1H), 7.42 -7.40 (m, 4H), 7.20 (d, J = 5.2 Hz, 1H) ), 2.54 (d, J = 5.2 Hz, 3H), 2.28 - 2.23 (m, 2H), 2.21 - 2.05 (m, 2H), 1.59 - 1.53 (m, 4H).

LRMS(ESI): Exact mass calcd for C17H20N4O4S [M+H] ⁺ 376.12, found 377.15.

<Example 45> N-methyl-1-(2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.55 (d, J = 5.2 Hz, 1H), 7.70 - 7.62 (m, 3H), 7.56 (d, J = 7.2 Hz, 1H), 7.43 -7.42 (m, 1H), 7.18 (d, J = 5.2 Hz) , 1H), 2.54 (d, J = 4.5 Hz, 3H), 2.23 - 2.18 (m, 2H), 2.21 - 2.04 (m, 2H), 1.59 -1.53 (m, 2H), 1.52 - 1.47 (m, 2H) ).

LRMS(ESI): Exact mass calcd for C18H18F3N3O2 [M+H] ⁺ 365.14, found 366.15.

<Example 46> 1-(5-fluoro-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.58 (d, J = 2.2 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.42 (s, 2H), 7.35 (m, 1H), 2.54 (d, J = 5.2 Hz, 3H), 2.17 - 2.07 (m, 4H), 1.67 - 1.59 (m, 2H), 1.52 - 1.47 (m, 2H).

LRMS(ESI): Exact mass calcd for C17H19FN4O4S [M+H] ⁺ 394.11, found 395.15.

<Example 47> 1-(5-methoxy-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.33 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.40 (s, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.03 (m, 1H), 3.78 (s, 3H) ), 2.52 (d, J = 5.2 Hz, 3H), 2.12 - 2.04 (m, 4H), 1.63 - 1.55 (m, 2H), 1.49 - 1.42 (m, 2H).

LRMS(ESI): Exact mass calcd for C18H22N4O5S [M+H] ⁺ 406.13, found 407.15.

<Example 48> 3-((4-(1-aminocyclohexyl)pyrimidin-2-yl)amino)benzenesulfonamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.13 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.36 (s, 2H), 8.29 (bs, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.52 -7.44 (m , 2H), 7.32 (s, 2H), 7.16 (d, J = 5.2 Hz, 1H), 2.30 - 2.25 (m, 2H), 1.84 - 1.81 (m, 2H), 1.70 - 1.68 (m, 2H), 1.53 - 1.46 (m, 4H).

LRMS(ESI): Exact mass calcd for C16H21N5O2S [M+H] ⁺ 347.14, found 348.15.

<Example 49> 4-(1-aminocyclohexyl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.18 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 8.36 (bs, 2H), 8.33 (s, 2H), 7.93 (d, J = 8.7 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H), 2.34 - 2.25 (m, 2H), 1.85 - 1.82 (m, 2H), 1.70 - 1.68 (m, 2H), 1.52 - 1.48 (m, 4H).

LRMS(ESI): Exact mass calcd for C17H19F3N4 [M+H] ⁺ 336.16, found 337.20.

<Example 50> 4-((4-(1-aminocyclohexyl)pyrimidin-2-yl)oxy)benzenesulfonamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.08 (d, J = 5.3 Hz, 1H), 8.46 (bs, 2H), 8.01 (d, J = 5.3 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 2.14 - 2.08 (m, 2H), 1.86 - 1.82 (m, 2H), 1.68 - 1.60 (m, 6H).

LRMS(ESI): Exact mass calcd for C16H20N4O3S [M+H] ⁺ 348.13, found 349.15.

<Example 51> N-methyl-1-(2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.56 (d, J = 5.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.43 -7.42 (m, 1H), 7.21 (d, J = 5.2 Hz, 1H), 3.27 (s, 3H), 2.54 (d, J = 4.5 Hz, 3H), 2.25 - 2.21 (m , 2H), 2.08 - 2.04 (m, 2H), 1.59 -1.51 (m, 4H).

LRMS(ESI): Exact mass calcd for C18H21N3O4S [M+H] ⁺ 375.13, found 376.15.

<Example 52> N-methyl-1-(2-(4-(methylsulfonyl)phenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.56 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 8.8 Hz, 2H), 8.50 (d, J = 8.8 Hz, 2H), 7.48-7.46 (m, 1H), 7.23 (d, J = 5.2 Hz, 1H), 3.27 (s, 3H), 2.55 (d, J = 4.5 Hz, 3H), 2.29 - 2.25 (m, 2H), 2.10 - 2.04 (m, 2H), 1.59 -1.53 (m, 4H).

LRMS(ESI): Exact mass calcd for C18H21N3O4S [M+H] ⁺ 375.13, found 376.15.

<Example 53> 1-(5-hydroxy-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.13 (s, 1H), 8.01 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.36 - 7.34 (m, 4H), 7.07 -7.03 (m, 1H), 2.54 (d, J = 4.5 Hz, 3H), 2.18 - 2.07 (m, 4H), 1.60 - 1.57 (m, 2H), 1.46 - 1.44 (m, 2H).

LRMS(ESI): Exact mass calcd for C17H20N4O5S [M+H] ⁺ 392.12, found 393.15.

<Example 54> 1-(2-(3-cyanophenoxy)-5-methoxypyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.35 (s, 1H), 7.77 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.63 - 7.58 (m, 2H), 6.99 (m, 1H), 3.78 (s, 3H), 2.52 (d, J = 5.2 Hz, 3H), 2.08 - 2.05 (m, 4H), 1.59 - 1.56 (m, 2H), 1.44 - 1.40 (m, 2H).

LRMS(ESI): Exact mass calcd for C19H20N4O3 [M+H] ⁺ 352.15, found 353.15.

<Example 55> 1-(5-methoxy-2-(4-(trifluoromethoxy)phenoxy)pyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.35 (s, 1H), 7.45 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.02 (m, 1H), 3.77 (s, 3H), 2.52 (d, J = 5.2 Hz, 3H), 2.08 - 2.05 (m, 4H), 1.60 - 1.52 (m, 2H), 1.43 - 1.37 (m, 2H).

LRMS(ESI): Exact mass calcd for C19H20F3N3O4 [M+H] ⁺ 411.14, found 412.15.

<Example 56> 1-(2-(3-cyanophenoxy)pyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.55 (d, J = 5.2 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.42 (m, 1H), 7.20 (d , J = 5.2 Hz, 1H), 2.55 (d, J = 5.2 Hz, 3H), 2.27 - 2.20 (m, 2H), 2.07 - 2.01 (m, 2H), 1.62 - 1.47 (m, 4H).

LRMS(ESI): Exact mass calcd for C18H18N4O2 [M+H] ⁺ 322.14, found 323.15.

<Example 57> N,2-dimethyl-2-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)propanamide

¹ H NMR (400 MHz, MeOD) δ; 8.62 (t, J = 1.8 Hz, 1H), 8.44 (d, J = 5.3 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.55 - 7.49 (m, 1H), 7.46 (t, J = 7.9 Hz) , 1H), 6.92 (d, J = 5.3 Hz, 1H), 2.75 (s, 3H), 1.60 (s, 6H).

LCMS (ESI): Exact mass calcd for C ₁₅ H ₁₉ N ₅ O ₃ S [M+H] ⁺ 349.12, found 350.10.

<Example 58> N,2-dimethyl-2-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)propanamide

¹ H NMR (400 MHz, MeOD) δ; 8.44 (d, J = 5.3 Hz, 1H), 7.92 - 7.85 (m, 2H), 7.85 - 7.76 (m, 2H), 6.92 (d, J = 5.3 Hz, 1H), 2.76 (s, 3H), 1.57 (s, 6H).

LCMS (ESI): Exact mass calcd for C ₁₅ H ₁₉ N ₅ O ₃ S [M+H] ⁺ 349.12, found 350.15.

<Example 59> N,2-dimethyl-2-(2-((4-sulfamoylphenoxy)pyrimidin-4-yl)propanamide

1H NMR (400 MHz, ^MeOD ) δ 8.57 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 5.2 Hz, 1H), 2.67 (s, 3H), 1.49 (s, 6H).

LCMS (ESI): Exact mass calcd for C ₁₈ H ₂₁ N ₃ O ₄ S [M+H] ⁺ 375.13, found 376.10.

<Example 60> 2-(5-methoxy-2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.72 (s, 1H), 8.22 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.54 -7.48 (m 2H), 3.85 (s, 3H), 2.74 (s, 3H), 1.58 ( s, 6H).

LCMS (ESI): Exact mass calcd for C ₁₆ H ₂₁ N ₅ O ₄ S [M+H] ⁺ 379.13, found 380.15.

<Example 61> 1-(5-methoxy-2-(3-(methylsulfonyl-phenoxy)pyrimidin-4-yl)-N-methylcyclopropane-1-carboxamide

¹ H NMR (400 MHz, MeOD) δ; 8.31 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.81 (t, J = 1.9 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.1 , 1.5 Hz, 1H), 3.96 (s, 3H), 3.17 (s, 3H), 2.70 (s, 3H), 1.47 (q, J = 4.3 Hz, 2H), 1.24 (q, J = 4.3 Hz, 2H) ).

LCMS (ESI): Exact mass calcd for C17H19N3O5S [M+H] ⁺ 377.10, found 378.10.

<Example 62> 1-(2-((3-cyano-5-fluorophenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopropane-1-carboxamide

¹ H NMR (400 MHz, MeOD) δ; 8.30 (s, 1H), 8.01 - 7.95 (m, 1H), 7.93 - 7.89 (m, 1H), 7.05 - 7.00 (m, 1H), 3.92 (s, 3H), 2.71 (s, 3H), 1.51 ( dd, J = 7.2, 4.1 Hz, 2H), 1.33 (dd, J = 7.4, 4.3 Hz, 2H).

LCMS (ESI): Exact mass calcd for C ₁₇ H ₁₅ FN ₄ O ₃ [M+H] ⁺ 341.12, found 342.10

<Example 63> 1-(2-((4-fluoro-3-(trifluoromenyl)phenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopropane-1- carboxamide

¹ H NMR (400 MHz, MeOD) δ; 8.15 (dd, J = 6.4, 2.8 Hz, 1H), 8.12 (s, 1H), 7.72 - 7.66 (m, 1H), 7.10 (t, J = 9.7 Hz, 1H), 3.78 (s, 3H), 2.58 (s, 3H), 1.37 (dd, J = 7.3, 4.2 Hz, 2H), 1.20 (dd, J = 7.3, 4.2 Hz, 2H).

LCMS (ESI): Exact mass calcd for C ₁₇ H ₁₆ F ₄ N ₄ O ₂ [M+H] ⁺ 384.12, found 385.10

<Example 64> 1-(5-methoxy-2-((2-methylpyridin-4-yl)oxy)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.73 (d, J = 6.4 Hz, 1H), 8.49 (s, 1H), 7.61 (s, 1H), 7.58 (d, J = 6.3 Hz, 1H), 7.06 (m, 1H), 3.85 (s, 3H) ), 2.62 (s, 3H), 2.52 (d, J = 5.2 Hz, 3H), 2.13 - 2.08 (m, 4H), 1.64 - 1.59 (m, 2H), 1.49 - 1.44 (m, 2H).

LRMS(ESI): Exact mass calcd for C18H22N4O3 [M+H] ⁺ 342.17, found 343.15.

<Example 65> 1-(5-methoxy-2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.79 (s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 7.93 (d, J = 9.5 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.01 (m, 1H), 3.75 (s, 3H), 3.16 (s, 3H), 2.52 (d, J = 5.2 Hz, 3H), 2.28 - 2.24 (m, 2H), 2.19 - 2.13 (m, 2H), 1.65 - 1.53 (m, 4H).

LRMS(ESI): Exact mass calcd for C19H24N4O4S [M+H] ⁺ 404.15, found 405.15.

<Example 66> 1-(5-methoxy-2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.87 (s, 1H), 8.25 (s, 1H), 7.92 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 6.96 (m, 1H), 3.76 (s, 3H) ), 3.07 (s, 3H), 2.52 (d, J = 5.2 Hz, 3H), 2.20 - 2.06 (m, 4H), 1.59 - 1.46 (m, 4H).

LRMS(ESI): Exact mass calcd for C19H24N4O4S [M+H] ⁺ 404.15, found 405.15.

<Example 67> 2-(5-methoxy-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.15 (s, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 3.77 (s, 3H), 2.61 (s, 3H), 1.32 (s, 6H) ).

LCMS (ESI): Exact mass calcd for C16H20N4O5S [M+H] ⁺ 380.12, found 381.15.

<Example 68> 2-(5-methoxy-2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.21 (s, 1H), 7.92 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H), 2.76 (s, 3H), 1.56 (s, 6H) ).

LCMS (ESI): Exact mass calcd for C16H21N5O4S [M+H] ⁺ 379.13, found 380.15.

<Example 69> 2-(5-methoxy-2-((4-methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.12 (s, 1H), 7.89 (d, J = 9.0 Hz, 2H), 7.72 (d, J = 9.0 Hz, 2H), 3.74 (s, 3H), 2.99 (s, 3H), 2.63 (s, 3H) ), 1.45 (s, 6H).

LCMS (ESI): Exact mass calcd for C17H22N4O4S [M+H] ⁺ 378.14, found 379.15.

<Example 70> 1-(5-methoxy-2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 11.14 (s, 1H), 8.47 (s, 1H), 8.45 (d, J = 7.0 Hz, 1H), 8.15 (bs, 1H), 7.95 (bs, 1H), 7.10 (m, 1H), 3.82 (s , 3H), 2.57 (s, 3H), 2.52 (d, J = 5.2 Hz, 3H), 2.23 - 2.20 (m, 4H), 1.70 - 1.64 (m, 2H), 1.62 - 1.56 (m, 2H).

LRMS(ESI): Exact mass calcd for C18H23N5O2 [M+H] ⁺ 341.19, found 342.20.

<Example 71> 1-(5-methoxy-2-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carb box amide

¹ H NMR (400 MHz, DMSO _- d6) δ; 10.27 (s, 1H), 8.44 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 8.32 (s, 1H), 7.71 (d, J = 5.4 Hz, 1H), 6.99 (m, 1H) ), 3.71 (s, 3H), 2.50 (d, J = 5.2 Hz, 3H), 2.17 - 2.09 (m, 4H), 1.64 - 1.56 (m, 2H), 1.54 - 1.49 (m, 2H).

LRMS(ESI): Exact mass calcd for C18H20F3N5O2 [M+H] ⁺ 395.16, found 396.20.

<Example 72> 1-(5-methoxy-2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopropane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.85 (s, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.18 (m 1H), 3.82 (s, 3H), 3.17 (s, 3H), 2.53 (s, 3H), 1.34 (q, J = 4.3 Hz, 2H), 1.17 (q, J = 4.3 Hz, 2H).

LCMS (ESI): Exact mass calcd for C17H20N4O4S [M+H] ⁺ 376.12, found 377.15.

<Example 73> 1-(2-((3-cyanophenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 9.75 (s, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.02 (m, 1H), 3.75 (s, 3H), 2.52 (d, J = 5.2 Hz, 3H), 2.26 - 2.13 (m, 4H), 1.67 - 1.62 (m, 2H) , 1.60 - 1.55 (m, 2H).

LRMS(ESI): Exact mass calcd for C19H21N5O2 [M+H] ⁺ 351.17, found 352.20.

<Example 74> 1-(2-((2-fluoro-5-methylphenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide

¹ H NMR (400 MHz, DMSO _- d6) δ; 8.53 (s, 1H), 8.21 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 8.2 Hz, 1H), 6.97 (m, 1H), 6.82 - 6.78 (m , 1H), 3.71 (s, 3H), 2.52 (d, J = 5.2 Hz, 3H), 2.26 (s, 3H), 2.21 - 2.16 (m, 2H), 2.13 - 2.07 (m, 2H), 1.64 - 1.60 (m, 2H), 1.56 - 1.52 (m, 2H).

LRMS(ESI): Exact mass calcd for C19H23FN4O2 [M+H] ⁺ 358.18, found 359.20.

<Example 75> 2-(5-methoxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.28 (s, 1H), 7.88 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 3.90 (s, 3H), 3.17 (s, 3H), 2.73 (s, 3H), 1.44 (s, 6H).

LRMS(ESI): Exact mass calcd for C17H21N3O5S [M+H] ⁺ 379.12, found 380.15.

<Example 76> 2-(5-methoxy-2-(4-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.16 (s, 1H), 7.91 (d, J = 6.8 Hz, 2H), 7.36 (d, J = 6.8 Hz, 2H), 3.79 (s, 3H), 3.05 (s, 3H), 2.62 (s, 3H) ), 1.34 (s, 6H).

LRMS(ESI): Exact mass calcd for C17H21N3O5S [M+H] ⁺ 379.12, found 380.15.

<Example 77> N,2-dimethyl-2-(2-(3-sulfamoylphenoxy)pyrimidin-4-yl)propanamide

¹ H NMR (400 MHz, MeOD) δ; 8.47 (d, J = 5.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.50 (t. J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 5.2 Hz, 1H), 2.56 (s, 3H), 1.39 (s, 6H).

LRMS(ESI): Exact mass calcd for C15H18N4O4S [M+H] ⁺ 350.10, found 351.15.

<Example 78> N,2-dimethyl-2-(2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)propanamide

¹ H NMR (400 MHz, MeOD) δ; 8.48 (d, J = 5.2 Hz, 1H), 7.76 - 7.74 (m, 2H), 7.60 (t. J = 8.1 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 3.06 (s, 1H), 2.57 (s, 3H), 1.39 (s, 6H).

LRMS(ESI): Exact mass calcd for C16H19N3O4S [M+H] ⁺ 349.11, found 350.15.

<Example 79> 2-(5-methoxy-2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide

1H NMR (400 MHz, ^MeOD ) δ 8.72 (d, J = 1.8 Hz, 1H), 8.22 (s, 1H), 7.86 - 7.81 (m, 1H), 7.55 - 7.47 (m, 2H), 3.85 (s , 3H), 3.13 (s, 3H), 2.74 (s, 3H), 1.58 (s, 6H).

LCMS (ESI): Exact mass calcd for C ₁₇ H ₂₂ N ₄ O ₄ S [M+H] ⁺ 378.14, found 379.15.

<Example 80> 2-(5-methoxy-2-((2-(methylpyridin-4-yl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.38 (s, 1H) 8.28 (d, J = 7.0 Hz, 1H), 8.09 (bs, 1H), 7.61 (s, 1H), 3.92 (s, 3H), 2.77 (d, J = 4.6 Hz, 3H) , 2.64 (s, 3H), 1.60 (s, 6H).

LCMS (ESI): Exact mass calcd for C16H21N5O2 [M+H] ⁺ 315.17, found 316.20.

<Example 81> 2-(5-methoxy-2-((2-(methylpyridin-4-yl)oxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.66 (d, J = 6.8 Hz, 1H), 8.45 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.72 (dd, J = 6.8, 2.5 Hz, 1H), 3.97 (s, 3H) ), 2.78 (s, 3H), 2.77 (s, 3H), 1.52 (s, 6H).

LCMS (ESI): Exact mass calcd for C16H20N4O3 [M+H] ⁺ 316.15, found 317.15.

<Example 82> N,2-dimethyl-2-(2-((2-methylpyridin-4-yl)oxy)pyrimidin-4-yl)propanamide

¹ H NMR (400 MHz, MeOD) δ; 8.63 (d, J = 5.2 Hz, 1H), 8.57 (d, J = 6.7 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.61 (dd, J = 6.7, 2.4 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 2.66 (s, 1H), 2.62 (s, 3H), 1.47 (s, 6H).

LCMS (ESI): Exact mass calcd for C15H18N4O2 [M+H] ⁺ 286.14, found 286.15.

<Example 83> 2-(2-(3-cyanophenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.58 (d, J = 5.2 Hz, 1H), 7.65 - 7.61 (m, 3H), 7.57 - 7.53 (m, 1H), 7.28 (d, J = 5.2 Hz, 1H), 2.71 (s, 3H), 1.51 (s, 6H).

LCMS (ESI): Exact mass calcd for C15H18N4O2 [M+H] ⁺ 296.13, found 297.15.

<Example 84> 2-(5-methoxy-2-((3-(sulfamoylphenyl)amino)pyrimidin-4-yl)-N,N,2-trimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.57 (s, 1H), 8.24 (s, 1H), 7.77 - 7.74 (m, 1H), 7.49 - 7.42 (m, 2H), 3.85 (s, 3H), 2.94 (s, 3H), 2.60 (s, 3H), 1.58 (s, 6H).

LCMS (ESI): Exact mass calcd for C17H23N5O4S [M+H] ⁺ 393.46, found 394.15.

<Example 85> 2-(5-methoxy-2-((4-(sulfamoylphenyl)amino)pyrimidin-4-yl)-N,N,2-trimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.26 (s, 1H), 7.91 (d, J = 8.92 Hz, 2H), 7.81 (d, J = 8.92 Hz, 2H), 3.87 (s, 3H), 2.95 (s, 3H), 2.59 (s, 3H) ), 1.57 (s, 6H).

LCMS (ESI): Exact mass calcd for C17H23N5O4S [M+H] ⁺ 393.46, found 394.20.

<Example 86> 2-(5-methoxy-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,N,2-trimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.31 (s, 1H), 7.79-7.77 (m, 1H), 7.73 - 7.72 (m, 1H), 7.62 (t, J = 8.00 Hz, 1H), 7.44 - 7.41 (m, 1H), 3.91 (s, 3H), 2.92 (s, 3H), 2.54 (s, 3H), 1.44 (s, 6H).

LCMS (ESI): Exact mass calcd for C17H22N4O5S [M+H] ⁺ 394.45, found 395.15.

<Example 87> 2-(5-methoxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,N,2-trimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.39 (s, 1H), 7.85-7.82 (m, 2H), (s, 1H), 7.74-7.70 (m, 1H), 7.58 - 7.55 (m, 1H), 3.91 (s, 3H), 3.17 (s , 3H), 2.92 (s, 3H), 2.54 (s, 3H), 1.44 (s, 6H).

LCMS (ESI): Exact mass calcd for C18H23N3O5S [M+H] ⁺ 393.46, found 394.15.

<Example 88> 2-(2-((3,4-dimethylisoxazol-5-yl)amino)-5-methoxypyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 7.97 (s, 1H), 3.70 (s, 3H), 2.61 (s, 3H), 2.11 (s, 3H), 1.78 (s, 3H), 1.37 (s, 6H).

LCMS (ESI): Exact mass calcd for C15H21N5O3 [M+H] ⁺ 319.16, found 320.20.

<Example 89> 2-(5-fluoro-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.43 (d, J = 2.6 Hz, 1H), 7.82 - 7.78 (m, 2H), 7.63 (t, J = 8.2 Hz, 1H), 7.45 (dd, J = 8.2, 2.4 Hz, 1H), 2.74 (d , J = 3.8 Hz, 3H), 1.50 (s, 6H).

LCMS (ESI): Exact mass calcd for C15H17FN4O4S [M+H] ⁺ 368.10, found 369.15.

<Example 90> 2-(5-methoxy-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.27 (s, 1H), 7.78 - 7.76 (m, 2H), 7.60 (t, J = 8.2 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 2.73 (s , 3H), 1.44 (s, 6H).

LCMS (ESI): Exact mass calcd for C16H20N4O5S [M+H] ⁺ 380.12, found 381.15.

<Example 91> 2-(5-hydroxy-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.02 (s, 1H), 7.74 - 7.72 (m, 2H), 7.59 (t, J = 8.2 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 2.70 (s, 3H), 1.45 (s , 6H).

LCMS (ESI): Exact mass calcd for C15H18N4O5S [M+H] ⁺ 366.10, found 367.15.

<Example 92> 2-(5-hydroxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.27 (s, 1H), 7.87 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 3.90 (s, 3H), 2.73 (s, 3H), 1.44 (s, 6H). LCMS (ESI): Exact mass calcd for C16H19N3O5S [M+H] ⁺ 365.10, found 366.15.

<Example 93> 2-(5-methoxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)propan-2-amine

¹ H NMR (400 MHz, MeOD) δ; 8.46 (s, 1H), 7.88 - 7.83 (m, 2H), 7.73 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 4.05 (s, 3H), 3.18 (s , 3H), 1.77 (s, 6H).

LCMS (ESI): Exact mass calcd for C15H19N3O4S [M+H] ⁺ 337.11, found 338.15.

<Example 94> 3-((4-(2-aminopropan-2-yl)-5-methoxypyrimidin-2-yl)oxy)benzenesulfonamide

¹ H NMR (400 MHz, MeOD) δ; 8.60 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.74 (s, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 4.05 (s, 3H), 3.18 (s, 3H), 1.76 (s, 6H).

LCMS (ESI): Exact mass calcd for C14H18N4O4S [M+H] ⁺ 338.10, found 339.15.

<Example 95> 2-(5-methoxy-2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)propan-2-amine

¹ H NMR (400 MHz, MeOD) δ; 8.45 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 4.04 (s, 3H), 1.76 (s, 6H).

LCMS (ESI): Exact mass calcd for C15H16F3N3O2 [M+H] ⁺ 327.12, found 328.15.

<Example 96> 2-(5-methoxy-2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide

¹ H NMR (400 MHz, MeOD) δ; 8.27 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H) 7.55 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.0 Hz) , 1H), 3.89 (s, 3H), 2.73 (s, 3H), 1.43 (s, 6H).

LCMS (ESI): Exact mass calcd for C17H18F3N3O3 [M+H] ⁺ 369.13, found 370.15.

<Example 97> 3-((4-(2-aminopropan-2-yl)-5-fluoropyrimidin-2-yl)oxy)benzenesulfonamide

¹ H NMR (400 MHz, MeOD) δ; 8.62 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.77 (s, 1H), 7.66 (t, J = 8.2 Hz, 1H), 1.79 (s, 6H).

LCMS (ESI): Exact mass calcd for C13H15FN4O3S [M+H] ⁺ 326.08, found 327.10.

<Example 98> 2-(5-fluoro-2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)propan-2-amine

¹ H NMR (400 MHz, MeOD) δ; 8.62 (d, J = 2.8 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.50 (t, J = 8.0 Hz, 1H), 1.79 (s, 6H).

LCMS (ESI): Exact mass calcd for C14H13F4N3O [M+H] ⁺ 315.10, found 316.10.

Structures of the Example compounds prepared in Examples 1 to 98 are summarized and shown in Table 1 below.

Example chemical structure Example chemical structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

<Experimental Example 1> Evaluation of anticancer activity

More than 90% of clear cell renal cell carcinoma (ccRCC) show inactivation of the pVHL tumor suppressor and is a major cause of malignancy. pVHL inactivation results in stabilization of the hypoxia-induced transcription factors HIF1α and HIF2α, inducing gene expression essential for the initiation and progression of ccRCC.

Here, there is PT2385 (control) as a specific HIF2α antagonist that blocks HIF1α/2α transcriptional dimerization, and PT2385 inhibits the expression of HIF2α-dependent genes including EPO, PAI-1 and VEGF in ccRCC cell lines.

In this experiment, the pyrimidine derivative compound of the present invention, using PT2385 as a control material, was tested as follows to evaluate the relative HIF2α transcriptional inhibitory activity and HIF2α lower target gene expression inhibitory activity.

<1-1> Evaluation of renal cancer cell line HIF2α transcriptional inhibitory activity

786-O cells (ccRcc) were dispensed into 6 well-plates at a concentration of 5 X 10 ⁵ cells/well, and one day later, 4 μg of pGL3 3xHRE and 200 ng of pGL3 control Renilla were transfected overnight. Thereafter, the cells were taken and dispensed into 96 well-plates at a concentration of 5 X 10 ³ cells/well, treated with the compound of the present invention at a concentration of 0.1 μM, and 48 hours later, luciferase using the Dual-Luciferase Reporter assay system (Promega #E1980). Analysis was performed, luciferase activity was measured using a Tecan i-control plate reader, and HIF2α transcriptional inhibitory activity was measured using 786-O, a renal cancer cell line of the compound of the present invention, and control substances ( PT-2385) compared to inhibition rate (% inhibition) and shown in Table 2.

<1-2> Evaluation of target gene expression inhibition activity

In order to evaluate the inhibitory activity of the compound of the present invention on the expression of EPO, PAI-1 and VEGF, which are sub-target genes of HIF2α contributing to cancer growth and survival, the following experiment was performed using RT-PCR.

786-O cells are dispensed into 6 well-plates at a concentration of 5 x 10 ⁵ cells/well (culture conditions: RPMI 1640 with 10% FBS, 1% Penicillin/Streptomycin). One day later, cells were treated with each compound at a concentration of 10 μM and incubated at 37° C. (final DMSO concentration kept at 0.1%). After 48 hours, RNA was extracted using Hybrid-R (Geneall #305-101). Synthesize cDNA using the High Capacity cDNA Reverse Transciption Kit (Thermo Fisher Scientific #4368814). React with Power SYBR Green PCR Mater Mix (Thermo Fisher Scientific #4367659) to perform real-time polymerase reaction (Real-time PCR) with StepOnePlus system. The expression levels of the target genes were normalized to GAPDH values and expressed as 2 ^-ΔΔCt values, and the inhibition rate (% inhibition) compared to the control substance (PT-2385) is shown in Table 2.

Example % inhibition compared to control substance (PT-2385) luciferase
activity
(in 0.1 µM) EPO
(in 10 µM) PAI-1
(in 10 µM) VEGF
(in 10 µM) One -3.6 2 15.3 3 -3.4 82 142 163 4 1.3 5 -4.5 6 -11.9 7 -0.8 8 4.0 9 -11.5 10 -155.7 11 1.1 12 -2.6 13 27.6 14 -22.4 15 -2.6 89 147 159 16 27.8 111 111 67 17 -2.9 83 139 158 18 -46.3 19 49 122 128 20 <0 <0 <0 21 <0 22 <0 23 <0 24 49 35 11 33 25 <0 26 <0 27 <0 28 30 33 <0 29 30 18.7 4 5 31 5.6 2 <0 32 <0 <0 <0 33 103 102 112 34 0 110 110 132 35 71 81 85 36 9.4 129 106 109 37 -5.9 82 88 71 38 -10.3 126 114 134 39 -15.1 119 102 117 40 -51.3 110 93 85 41 -20.3 83 72 66 42 101 86 76 43 94 82 72 44 -13.4 48 59 37 45 -13.3 97 87 83 46 -4.6 55 70 55 47 -8.2 95 105 92 48 -10.7 47 56 63 49 55 93 86 94 50 6.9 102 102 101 51 -11.7 96 91 97 52 -18.4 95 85 94 53 83 62 56 54 -8.6 110 107 119 55 -12.7 92 83 79 56 -4.8 95 100 102 57 86 94 72 58 41 102 96 113 59 24.6 84 96 94 60 37 114 107 114 61 88 81 88 62 63 72 70 63 61 67 67 64 -7.6 65 -22.6 66 18.3 67 68 68.8 69 5.1 70 107 104 115 71 80 74 81 72 98 95 95 73 91 87 81 74 99 97 84 75 49.8 76 33.3 77 26.5 78 37.4 79 51.6 80 22.2 81 3.8 82 30.5 83 24.9 84 24.7 85 -1.0 86 -12.9 87 12.4 88 4.4 89 90 0.5 91 1.5 92 4.8 93 15.2 94 14.6 95 2.1 96 1.9 97 2.0 98 1.6

As confirmed in Table 2, the pyrimidine derivative compound of the present invention was confirmed to effectively inhibit the expression of the HIF2α sub-target gene contributing to cancer growth and survival, and compared to the conventional control substance (PT2385), it exhibited excellent anti-cancer properties. activity is confirmed.

Claims (12)

A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1 above,
R ₁ is hydrogen, halogen, hydroxy, or C _1-5 straight or branched chain alkoxy;

L is methylene;

,

,

, or

ego;

R ₂ is hydrogen, -NH ₂ ,

, or

ego;
Wherein A ₁ is C _1-5 straight or branched chain alkyl;
A ₂ and A ₃ are independently hydrogen, C _1-5 straight-chain or branched-chain alkyl, C _1-5 straight-chain or branched-chain alkoxy, phenyl, unsubstituted or substituted C _3-6 cycloalkyl,
The substituent of the substituted C _3-6 cycloalkyl is -CN;

X is -NH- or -O-; and

Ar is unsubstituted, substituted or fused phenyl, or
An unsubstituted or substituted 5-6 membered heteroaryl containing at least one heteroatom selected from the group consisting of N and O;
The substituted phenyl is halogen, -CF ₃ , -CN, -OCF ₃ , C _1-5 straight-chain or branched-chain alkyl, aminosulfonyl, methylsulfonyl, methylamino, dimethylamino, C _1-3 alkylcarbonyl and C _2-5 phenyl substituted with one or more substituents selected from the group consisting of alkenylcarbonylamino;
The fused phenyl is a 5-membered heteroaryl containing at least one N, and the fused 5-6 membered heteroaryl is C _1-5 straight-chain or branched-chain alkyl and -CF ₃ One or more substituents selected from the group consisting of is a substituted C _5-6 heteroaryl).
According to claim 1,
wherein R ₁ is hydrogen, halogen, hydroxy, or C _1-3 straight-chain or branched-chain alkoxy;
Wherein A ₁ is C _1-3 straight-chain or branched-chain alkyl;
A ₂ and A ₃ are independently hydrogen, C _1-3 straight-chain or branched-chain alkyl, C _1-3 straight-chain or branched-chain alkoxy, phenyl, unsubstituted or substituted C _3-4 cycloalkyl,
The substituent of the substituted C _3-4 cycloalkyl is -CN; and
Wherein Ar is unsubstituted, substituted or fused phenyl, or
An unsubstituted or substituted 5-6 membered heteroaryl containing at least one heteroatom selected from the group consisting of N and O;
The substituted phenyl is halogen, -CF ₃ , -CN, -OCF ₃ , C _1-4 straight-chain or branched-chain alkyl, aminosulfonyl, methylsulfonyl, methylamino, dimethylamino, C _1-2 alkylcarbonyl and C _2-4 phenyl substituted with one or more substituents selected from the group consisting of alkenylcarbonylamino;
The fused phenyl is a phenyl fused with a 5-membered heteroaryl containing at least one N,
The substituted 5-6 membered heteroaryl is C _1-4 straight-chain or branched-chain alkyl and -CF ₃ One or more substituents selected from the group consisting of substituted C _5-6 heteroaryl, characterized in that ,
A compound or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₁ is -H, -F, -OH, or -OCH ₃ ;
R ₂ is -H;

,

,

,

,

,

,

,

, or

ego; and

Ar is

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

characterized in that,
A compound or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound represented by Formula 1,
A compound or a pharmaceutically acceptable salt thereof, characterized in that it is any one compound selected from the group of compounds below.
(1) ethyl 1-(2-(phenylamino)pyrimidin-4-yl)cyclohexane-1-carboxylate;
(2) ethyl 1-(2-((3-chlorophenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;
(3) ethyl 1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;
(4) ethyl 1-(2-((4-chloro-3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;
(5) ethyl 1-(2-((4-fluoro-3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;
(6) ethyl 1-(2-((3-fluorophenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;
(7) ethyl 1-(2-((3-chloro-5-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;
(8) ethyl-1-(2-((3-fluorophenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;
(9) ethyl 1-(2-((4-fluoro-3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;
(10) 4-cyclopentyl-N-(3-fluorophenyl)pyrimidin-2-amine;
(11) 4-cyclopentyl-N-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-amine;
(12) 4-cyclohexyl-N-phenylpyrimidin-2-amine;
(13) 3-((4-cyclohexylpyrimidin-2-yl)amino)benzenesulfonamide;
(14) N-(4-chloro-3-(trifluoromethyl)phenyl)-4-cyclohexylpyrimidin-2-amine;
(15) ethyl 1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;
(16) ethyl 1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;
(17) 3-((4-cyclopentylpyrimidin-2-yl)amino)benzenesulfonamide;
(18) 4-((4-cyclopentylpyrimidin-2-yl)amino)benzenesulfonamide;
(19) ethyl 1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylate;
(20) ethyl 1-(2-((4-acrylamidophenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;
(21) N-(1-cyanocyclopropyl)-1-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(22) N-ethyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(23) N-ethyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(24) 1-(2-((3-acetylphenyl)amino)pyrimidin-4-yl)-N-ethylcyclopentane-1-carboxamide;
(25) 1-(2-((1H-indazol-5-yl))amino)pyrimidin-4-yl)-N-ethylcyclopentane-1-carboxamide;
(26) N-phenyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(27) N-phenyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(28) ethyl 1-(2-((3-acetylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;
(29) ethyl 1-(2-((1H-indazol-5-yl))amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;
(30) ethyl 1-(2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;
(31) ethyl 1-(2-((3-cyano-5-fluorophenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxylate;
(32) N-methoxy-N-methyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(33) N-methyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(34) N-methyl-1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide;
(35) N-methyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide;
(36) N-methyl-1-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(37) 1-(2-((3-acetylphenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(38) N-methyl-1-(2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(39) N-methyl-1-(2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(40) 1-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(41) 4-((4-(1-aminocyclohexyl)pyrimidin-2-yl)amino)benzenesulfonamide;
(42) 1-(2-((4-(dimethylamino)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(43) 1-(2-((3-fluoro-4-sulfamoylphenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(44) N-methyl-1-(2-(4-sulfamoylphenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(45) N-methyl-1-(2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(46) 1-(5-fluoro-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(47) 1-(5-methoxy-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(48) 3-((4-(1-aminocyclohexyl)pyrimidin-2-yl)amino)benzenesulfonamide;
(49) 4-(1-aminocyclohexyl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine;
(50) 4-((4-(1-aminocyclohexyl)pyrimidin-2-yl)oxy)benzenesulfonamide;
(51) N-methyl-1-(2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(52) N-methyl-1-(2-(4-(methylsulfonyl)phenoxy)pyrimidin-4-yl)cyclopentane-1-carboxamide;
(53) 1-(5-hydroxy-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide;
(54) 1-(2-(3-cyanophenoxy)-5-methoxypyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide;
(55) 1-(5-methoxy-2-(4-(trifluoromethoxy)phenoxy)pyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide;
(56) 1-(2-(3-cyanophenoxy)pyrimidin-4-yl)-N-methylcyclopenta-1-carboxamide;
(57) N,2-dimethyl-2-(2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)propanamide;
(58) N,2-dimethyl-2-(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)propanamide;
(59) N,2-dimethyl-2-(2-((4-sulfamoylphenoxy)pyrimidin-4-yl)propanamide;
(60) 2-(5-methoxy-2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(61) 1-(5-methoxy-2-(3-(methylsulfonyl-phenoxy)pyrimidin-4-yl)-N-methylcyclopropane-1-carboxamide;
(62) 1-(2-((3-cyano-5-fluorophenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopropane-1-carboxamide;
(63) 1-(2-((4-fluoro-3-(trifluoromenyl)phenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopropane-1-carbox amides;
(64) 1-(5-methoxy-2-((2-methylpyridin-4-yl)oxy)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(65) 1-(5-methoxy-2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(66) 1-(5-methoxy-2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(67) 2-(5-methoxy-2-(4-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(68) 2-(5-methoxy-2-((4-sulfamoylphenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(69) 2-(5-methoxy-2-((4-methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(70) 1-(5-methoxy-2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(71) 1-(5-methoxy-2-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide ;
(72) 1-(5-methoxy-2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N-methylcyclopropane-1-carboxamide;
(73) 1-(2-((3-cyanophenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(74) 1-(2-((2-fluoro-5-methylphenyl)amino)-5-methoxypyrimidin-4-yl)-N-methylcyclopentane-1-carboxamide;
(75) 2-(5-methoxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(76) 2-(5-methoxy-2-(4-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(77) N,2-dimethyl-2-(2-(3-sulfamoylphenoxy)pyrimidin-4-yl)propanamide;
(78) N,2-dimethyl-2-(2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)propanamide;
(79) 2-(5-methoxy-2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(80) 2-(5-methoxy-2-((2-(methylpyridin-4-yl)amino)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(81) 2-(5-methoxy-2-((2-(methylpyridin-4-yl)oxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(82) N,2-dimethyl-2-(2-((2-methylpyridin-4-yl)oxy)pyrimidin-4-yl)propanamide;
(83) 2-(2-(3-cyanophenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(84) 2-(5-methoxy-2-((3-(sulfamoylphenyl)amino)pyrimidin-4-yl)-N,N,2-trimethylpropanamide;
(85) 2-(5-methoxy-2-((4-(sulfamoylphenyl)amino)pyrimidin-4-yl)-N,N,2-trimethylpropanamide;
(86) 2-(5-methoxy-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,N,2-trimethylpropanamide;
(87) 2-(5-methoxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,N,2-trimethylpropanamide;
(88) 2-(2-((3,4-dimethylisoxazol-5-yl)amino)-5-methoxypyrimidin-4-yl)-N,2-dimethylpropanamide;
(89) 2-(5-fluoro-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(90) 2-(5-methoxy-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(91) 2-(5-hydroxy-2-(3-sulfamoylphenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(92) 2-(5-hydroxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(93) 2-(5-methoxy-2-(3-(methylsulfonyl)phenoxy)pyrimidin-4-yl)propan-2-amine;
(94) 3-((4-(2-aminopropan-2-yl)-5-methoxypyrimidin-2-yl)oxy)benzenesulfonamide;
(95) 2-(5-methoxy-2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)propan-2-amine;
(96) 2-(5-methoxy-2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)-N,2-dimethylpropanamide;
(97) 3-((4-(2-aminopropan-2-yl)-5-fluoropyrimidin-2-yl)oxy)benzenesulfonamide; and
(98) 2-(5-fluoro-2-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)propan-2-amine.
A pharmaceutical composition for preventing or treating cancer containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
According to claim 5,
The pharmaceutical composition, characterized in that the cancer is a cancer associated with heteromerization between HIF2α and ARNT.
According to claim 5,
The pharmaceutical composition, characterized in that the compound prevents or treats cancer by inhibiting heteromerization between HIF2α and ARNT.
According to claim 5,
The pharmaceutical composition, characterized in that the cancer is renal cancer.
A health functional food composition for preventing or improving cancer containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
According to claim 9,
The health functional food composition, characterized in that the cancer is a cancer related to heteromerization between HIF2α and ARNT.
According to claim 9,
The health functional food composition, characterized in that the compound prevents or treats cancer by inhibiting heteromerization between HIF2α and ARNT.
According to claim 9,
The health functional food composition, characterized in that the cancer is renal cancer.